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APOE -Related total cholesterol levels response to a multifactorial therapy in patients with dementia.
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About 80% of functional genes in the human genome are expressed in the brain and over 1,200 different genes have been associated with the pathogenesis of CNS disorders and dementia. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variations in specific candidate genes and the positive and a...
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... with dementia (N=765, age: 69.44 ± 9.15 years, range: 50-96 years; 466 females, age: 69.18 ± 9.19 years, range: 50-96 years; and 299 males, age: 69.85 ± 9.09 years, range: 50-91 years; p < 0.01) received for three months a multifactorial therapy integrated by CDP-choline (500 mg/day, p.o.), Nicergoline (5 mg/day, p.o.), Sardilipin (E-SAR-94010)(LipoEsar ® )(250 mg, t.i.d.), and Animon Complex ® (2 capsules/day), a nutraceutical compound integrated by a purified extract of Chenopodium quinoa (250 mg), ferrous sulphate (38.1 mg equivalent to 14 mg of iron), folic acid (200 μg), and vitamin B 12 (1 μg) per capsule (RGS: 26.06671/C). Patients with chronic deficiency of iron (<35 μg/mL), folic acid (<2.5 ng/mL) or vitamin B 12 (<150 pg/mL) received an additional supplementation of iron (80 mg/day), folic acid (5 mg/day) and B complex vitamins (B 1 , 15 mg/day; B 2 , 15 mg/day; B 6 , 10 mg/day; B 12 , 10 μg/day; nicotinamide, 50 mg/day), respectively, to maintain stable levels of serum iron (50–150 μg/mL), folic acid (5–20 ng/mL) and vitamin B 12 levels (500–1000 pg/mL) in order to avoid the negative influence of all these metabolic factors on cognition [102,103]. Patients with hypertension (>150/85 mmHg) received Enalapril (20 mg/day). The frequency of APOE genotypes was: APOE-2/3 , 7.97%; APOE-2/4 , 1.18%; APOE-3/3 , 58.95%; APOE-3/4 , 27.32%; and APOE-4/4 , 4.58% (Figure 1). Blood pressure, psychometric assessment (Mini-Mental State Examination, MMSE; ADAS; Hamilton Rating Scale-Depression, HAM-D; Hamilton Rating Scale-Anxiety, HAM-A), and blood parameters (glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglyceride, iron, folate, vitamin B 12 , TSH, T 4 ) were evaluated at baseline and after 3 months of treatment. Systolic (p < 0.0002) and diastolic blood pressure (p < 0.001), cognitive function (as assessed by MMSE, 20.51 ± 6.51 vs. 21.45 ± 6.95, p < 0.0000000001; ADAS-Cog, 22.94 ± 13.87 vs. 21.23 ± 12.84, p < 0.0001; ADAS-Non-Cog, 5.26 ± 4.18 vs. 4.15 ± 3.63, p < 0.0000000001; ADAS-Total, 27.12 ± 16.93 vs. 24.28 ± 15.06, p < 0.00009), and mood (HAM-A, 11.35 ± 5.44 vs. 9.79 ± 4.33, p < 0.0000000001; HAM-D, 10.14 ± 5.23 vs. 8.59 ± 4.30, p < 0.0000000001) improved after treatment. Glucose levels did not change. Total cholesterol levels (224.78 ± 45.53 vs. 203.64 ± 39.69 mg/dL, p < 0.0000000001), HDL-cholesterol levels (54.11 ± 14.54 vs. 52.54 ± 14.86 mg/dL, p < 0.0001), and LDL-cholesterol levels (148.15 ± 39.13 vs. 128.89 ± 34.83 mg/dL, p < 0.0000000001) were significantly reduced, whereas triglyceride levels increased (111.99 ± 67.14 vs. 120.69 ± 67.14 mg/dL, p < 0.0006) after 3 months of combined treatment. Folate (7.07 ± 3.61 vs. 18.14 ± 4.23 ng/mL, p < 0.000000001) and vitamin B 12 levels (459.65 ± 205.80 vs. 689.78 ± 338.82 pg/mL, p < 0.000000001) also increased, and both TSH and T 4 levels remained unchanged after treatment. The response rate in terms of cognitive improvement was as follows: 59.74% responders (RRs), 24.44% non-responders (NRs), and 15.82% stable responders (SRs)(no change in MMSE score after three months of treatment). The response rate in cholesterol levels was very similar: 57.78% RRs, 28.50% NRs, and 13.72% SRs. In this study, the basal MMSE score differed in APOE-2/3 carriers with respect to APOE-2/4 (p < 0.02), APOE-3/4 (p < 0.004), and APOE-4/4 carriers (p < 0.0009); in APOE-3/3 vs. APOE-3/4 (p < 0.0005), and APOE-3/3 vs. APOE-4/4 (p < 0.002). The best responders were APOE-3/3 (p < 0.0000000001) > APOE-3/4 (p < 0.00001) > APOE-4/4 carriers (p < 0.05). Patients harboring the APOE-2/3 and APOE-2/4 genotypes did not show any significant improvement. The response rate ...
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... highest cholesterol levels were seen in APOE-4/4 > APOE-3/4 > APOE-3/3. All patients showed a clear reduction in cholesterol levels after treatment with Sardilipin. This was particularly significant in APOE-3/3 (p < 0.0000000001) > APOE-3/4 (p < 0.00000008) > APOE-4/4 (p < 0.002) > APOE-2/3 (p < 0.02) > APOE-2/4 carriers (p: 0.26) (Figure 1). The response rate by genotype was as follows: APOE-2/3 : 63.93% RRs, 29.51% NRs, 6.56% SRs; APOE-2/4 : 44.44% RRs, 22.22% NRs, 33.34% SRs; APOE-3/3 : 54.32% RRs, 28.16% NRs, 17.52% SRs; APOE-3/4 : 53.59% RRs, 31.58% NRs, 14.83% SRs; APOE-4/4 : 65.71% RRs, 20.00% NRs, 14.29% SRs. HDL-cholesterol levels significantly decreased in APOE-3/3 (p < 0.001) > APOE-3/4 (p < 0.05), with no significant changes in patients with other genotypes. In contrast, LDL-cholesterol levels showed identical changes to those observed in total cholesterol, with similar differences among genotypes at baseline and almost identical decreased levels after treatment ( APOE-3/3 , p > 0.0000000001; > APOE-3/4 , p < 0.00001; > APOE-2/3 , p < 0.0004; > APOE-4/4 , p < 0.001; > APOE-2/4 , p:0.31). Paradoxically, triglyceride levels tended to increase in all APOE genotypes ( APOE-3/3 , p < 0.01; > APOE-4/4 , p < 0.03; > APOE-2/3 , p:0.12; > APOE-3/4 , p:0.17), except in APOE-2/4 carriers, who showed a tendency to decrease. Basal triglyceride levels were significantly lower in APOE-4/4 carriers than in APOE-2/3 (p < 0.03) and APOE-3/4 carriers (p < 0.04). Sardilipin (E-SAR-94010, LipoEsar ® , LipoSea ® ) is a natural product extracted from the marine species Sardina pilchardus , by means of non-denaturing biotechnological procedures [193]. The main chemical compounds of LipoEsar ® are lipoproteins (60–80%) whose micelle structure probably mimics that of physiological lipoproteins involved in lipid metabolism. In preclinical studies, sardilipin has shown to be effective in (i) reducing blood cholesterol (CHO), triglyceride (TG), uric acid (UA), and glucose (Glu) levels, as well as liver alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity; (ii) enhancing immunological function by regulating both lymphocyte and microglia activity; (iii) inducing antioxidant effects mediated by superoxide dismutase activity; and (iv) improving cognitive function [16,193,194]. According to these results, it appears that the therapeutic response of patients with dyslipidemia to sardilipin is APOE -related. The best responders were patients with APOE-3/3 > APOE-3/4 > APOE-4/4 . Patients with the other APOE genotypes ( 2/2 , 2/3 , 2/4 ) did not show any hypolipemic response to this novel compound [16,194]. In patients with dementia, the effects of sardilipin were very similar to those observed in patients with chronic dyslipidemia, suggesting that the lipid-lowering properties of sardilipin are APOE -dependent (Figure 1). Clinical studies have revealed that sardilipin reduces blood total cholesterol (T-CHO) (20–30%), Glu (5–10%), UA (10–15%), TG (30–50%), ALT and AST, after 1–3 months of treatment at a daily dose of 250–500 mg (t.i.d). The effect on T-CHO is the result of decreasing LDL-CHO levels and increasing HDL-CHO levels in parallel with an improvement in hepatic protection reflected by reduction in ALT, AST, and GGT activity, as the result of reducing liver steatosis. Both LDL and HDL levels are modulated by dietary, behavioral and genetic factors [16]. Most of these therapeutic effects on the regulation of lipid metabolism tend to show an age-dependent pattern and are also associated with specific genomic profiles in the population. In addition, sardilipin diminishes the size of xanthelasma plaques by 30–60% after 6–9 months of treatment, and specifically protects against the hepatotoxicity induced by statins. Similar effects can be observed on atheromatous plaques on ...
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... highest cholesterol levels were seen in APOE-4/4 > APOE-3/4 > APOE-3/3. All patients showed a clear reduction in cholesterol levels after treatment with Sardilipin. This was particularly significant in APOE-3/3 (p < 0.0000000001) > APOE-3/4 (p < 0.00000008) > APOE-4/4 (p < 0.002) > APOE-2/3 (p < 0.02) > APOE-2/4 carriers (p: 0.26) (Figure 1). The response rate by genotype was as follows: APOE-2/3 : 63.93% RRs, 29.51% NRs, 6.56% SRs; APOE-2/4 : 44.44% RRs, 22.22% NRs, 33.34% SRs; APOE-3/3 : 54.32% RRs, 28.16% NRs, 17.52% SRs; APOE-3/4 : 53.59% RRs, 31.58% NRs, 14.83% SRs; APOE-4/4 : 65.71% RRs, 20.00% NRs, 14.29% SRs. HDL-cholesterol levels significantly decreased in APOE-3/3 (p < 0.001) > APOE-3/4 (p < 0.05), with no significant changes in patients with other genotypes. In contrast, LDL-cholesterol levels showed identical changes to those observed in total cholesterol, with similar differences among genotypes at baseline and almost identical decreased levels after treatment ( APOE-3/3 , p > 0.0000000001; > APOE-3/4 , p < 0.00001; > APOE-2/3 , p < 0.0004; > APOE-4/4 , p < 0.001; > APOE-2/4 , p:0.31). Paradoxically, triglyceride levels tended to increase in all APOE genotypes ( APOE-3/3 , p < 0.01; > APOE-4/4 , p < 0.03; > APOE-2/3 , p:0.12; > APOE-3/4 , p:0.17), except in APOE-2/4 carriers, who showed a tendency to decrease. Basal triglyceride levels were significantly lower in APOE-4/4 carriers than in APOE-2/3 (p < 0.03) and APOE-3/4 carriers (p < 0.04). Sardilipin (E-SAR-94010, LipoEsar ® , LipoSea ® ) is a natural product extracted from the marine species Sardina pilchardus , by means of non-denaturing biotechnological procedures [193]. The main chemical compounds of LipoEsar ® are lipoproteins (60–80%) whose micelle structure probably mimics that of physiological lipoproteins involved in lipid metabolism. In preclinical studies, sardilipin has shown to be effective in (i) reducing blood cholesterol (CHO), triglyceride (TG), uric acid (UA), and glucose (Glu) levels, as well as liver alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity; (ii) enhancing immunological function by regulating both lymphocyte and microglia activity; (iii) inducing antioxidant effects mediated by superoxide dismutase activity; and (iv) improving cognitive function [16,193,194]. According to these results, it appears that the therapeutic response of patients with dyslipidemia to sardilipin is APOE -related. The best responders were patients with APOE-3/3 > APOE-3/4 > APOE-4/4 . Patients with the other APOE genotypes ( 2/2 , 2/3 , 2/4 ) did not show any hypolipemic response to this novel compound [16,194]. In patients with dementia, the effects of sardilipin were very similar to those observed in patients with chronic dyslipidemia, suggesting that the lipid-lowering properties of sardilipin are APOE -dependent (Figure 1). Clinical studies have revealed that sardilipin reduces blood total cholesterol (T-CHO) (20–30%), Glu (5–10%), UA (10–15%), TG (30–50%), ALT and AST, after 1–3 months of treatment at a daily dose of 250–500 mg (t.i.d). The effect on T-CHO is the result of decreasing LDL-CHO levels and increasing HDL-CHO levels in parallel with an improvement in hepatic protection reflected by reduction in ALT, AST, and GGT activity, as the result of reducing liver steatosis. Both LDL and HDL levels are modulated by dietary, behavioral and genetic factors [16]. Most of these therapeutic effects on the regulation of lipid metabolism tend to show an age-dependent pattern and are also associated with specific genomic profiles in the population. In addition, sardilipin diminishes the size of xanthelasma plaques by 30–60% after 6–9 months of treatment, and specifically protects against the hepatotoxicity induced by statins. Similar effects can be observed on atheromatous plaques on ...
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Schizophrenia is a severe mental disorder that often manifests within the first three decades of life. Its prognosis is uncertain and may result in a prolonged treatment that could extend throughout the entire lifespan of the patient. Antipsychotic drugs are characterized by a high interindividual variability when considering therapeut...
To determine the role of CYP450 copy number variation (CNV) beyond CYP2D6, 11 CYP450 genes were interrogated by multiplex ligation-dependent probe amplification and quantitative PCR in 542 African-American, Asian, Caucasian, Hispanic and Ashkenazi Jewish individuals. The CYP2A6, CYP2B6 and CYP2E1 combined deletion/duplication allele frequencies ran...
Citations
... One primary obstacle lies in the limited empirical substantiation [51]. While various pharmacogenomic investigations have been conducted in Alzheimer's disease, the modest scale of many studies and their potential lack of universal applicability hinder the robust evidence needed to confidently shape clinical decisions [52][53][54]. Furthermore, the intricate complexity of Alzheimer's disease, shaped by an interplay of genetic and environmental elements, adds a dimension of intricacy to the realm of pharmacogenomics Though pharmacogenomics furnishes valuable insights into potential medication responses, it's unable to encompass the full scope of influences that contribute to treatment outcomes. ...
Alzheimer's disease (AD) stands as an intricate neurodegenerative condition impacting numerous individuals globally. In pursuit of enhancing the efficacy and safety of AD treatments, pharmacogenomic strategies have emerged. These methods encompass the identification of genetic variations influencing drug metabolism, the utilization of genetic testing to spot individuals vulnerable to AD, and the pinpointing of potential drug targets grounded in the genetic underpinnings of the ailment. As a demonstration, differences in the genetic variations present within the CYP2D6 gene can mold the processing of donepezil- an extensively employed cholinesterase inhibitor crucial in the treatment of AD. Identifying these genetic nuances can potentially facilitate personalized dosing or the exploration of alternative drugs. Correspondingly, genetic tests targeting the APOE gene can unmask individuals at a heightened risk of developing AD, enabling early interventions to deter or postpone the onset of the condition. Lastly, leveraging insights into the genetic origins of the disease, pharmaceuticals targeting the beta-amyloid protein, which accumulates in the brains of AD patients, are being crafted.Collectively, pharmacogenomic approaches harbor the potential to refine AD treatment by customizing therapy according to each individual's genetic blueprint.
... The pathogenic load of APOE-4 affects 35-40% of cases, with significant phenotypic consequences (Tables 2-4). APOE-4/4 carriers tend to show an earlier age-at-onset in >80% of the cases; lower peripheral ApoE, nitric oxide, histamine, Aβ, HDL-cholesterol, and triglyceride levels; higher levels of total cholesterol and LDL-cholesterol; more pronounced brain atrophy and slower brain bioelectrical activity; more severe brain hemodynamic dysfunction represented by hypoperfusion, reduced brain blood flow velocity and increased pulsatility and resistance indices; increased lymphocyte apoptosis; faster cognitive deterioration; more frequent metabolic disorders, cardiovascular disorders, hypertension, atherosclerosis, liver metabolism dysfunction, behavioral disturbances, and alterations in circadian rhythm patterns; and a poor response to conventional treatments [5,[11][12][13]22,48,[59][60][61][62][63][64][65][66][67][68][69][70][71]. ...
... The low diagnostic value of DNA methylation is compensated for by the exquisite sensitivity of this biomarker that responds in a highly sensitive The pathogenic load of APOE-4 affects 35-40% of cases, with significant phenotypic consequences (Tables 2-4). APOE-4/4 carriers tend to show an earlier age-at-onset in >80% of the cases; lower peripheral ApoE, nitric oxide, histamine, Aβ, HDL-cholesterol, and triglyceride levels; higher levels of total cholesterol and LDL-cholesterol; more pronounced brain atrophy and slower brain bioelectrical activity; more severe brain hemodynamic dysfunction represented by hypoperfusion, reduced brain blood flow velocity and increased pulsatility and resistance indices; increased lymphocyte apoptosis; faster cognitive deterioration; more frequent metabolic disorders, cardiovascular disorders, hypertension, atherosclerosis, liver metabolism dysfunction, behavioral disturbances, and alterations in circadian rhythm patterns; and a poor response to conventional treatments [5,[11][12][13]22,48,[59][60][61][62][63][64][65][66][67][68][69][70][71]. ...
... Brain damage and increased cognitive deterioration are currently associated with cardiovascular disorders and blood pressure changes in AD [90,91]. APOE-4 carriers with dementia also exhibit cardiovascular disorders, atherosclerosis, and cerebrovascular damage [5,12,[43][44][45][60][61][62][63][64][65][66]92]. Lipid metabolism disorders contribute to the cerebrovascular component of AD. ...
Alzheimer’s disease (AD) is a priority health problem with a high cost to society and a large consumption of medical and social resources. The management of AD patients is complex and multidisciplinary. Over 90% of patients suffer from concomitant diseases and require personalized therapeutic regimens to reduce adverse drug reactions (ADRs), drug–drug interactions (DDIs), and unnecessary costs. Men and women show substantial differences in their AD-related phenotypes. Genomic, epigenetic, neuroimaging, and biochemical biomarkers are useful for predictive and differential diagnosis. The most frequent concomitant diseases include hypertension (>25%), obesity (>70%), diabetes mellitus type 2 (>25%), hypercholesterolemia (40%), hypertriglyceridemia (20%), metabolic syndrome (20%), hepatobiliary disorder (15%), endocrine/metabolic disorders (>20%), cardiovascular disorder (40%), cerebrovascular disorder (60–90%), neuropsychiatric disorders (60–90%), and cancer (10%). Over 90% of AD patients require multifactorial treatments with risk of ADRs and DDIs. The implementation of pharmacogenetics in clinical practice can help optimize the limited therapeutic resources available to treat AD and personalize the use of anti-dementia drugs, in combination with other medications, for the treatment of concomitant disorders.
... Our study corroborates the assertion that APOE is a major, but not exclusive, pathogenic determinant of the pharmacogenetic outcome in AD and that APOE-4 carriers are at biological disadvantage with respect to patients harboring the APOE-3 allele, as previously documented [2,4,6,18,[34][35][36][37][49][50][51]. Most studies, where AD patients were treated with multifactorial combinations, revealed that APOE-3/3 carriers are the best responders and APOE-4/4 carriers are the worst responders. ...
Background:
Mood disorders represent a risk factor for dementia and are present in over 60% of cases with Alzheimer's disease (AD). More than 80% variability in drug pharmacokinetics and pharmacodynamics is associated with pharmacogenetics.
Methods:
Anxiety and depression symptoms were assessed in 1006 patients with dementia (591 females, 415 males) and the influence of pathogenic (APOE) and metabolic (CYP2D6, CYP2C19, and CYP2C9) gene variants on the therapeutic outcome were analyzed after treatment with a multifactorial regime in a natural setting.
Results and conclusions:
(i) Biochemical, hematological, and metabolic differences may contribute to changes in drug efficacy and safety; (ii) anxiety and depression are more frequent and severe in females than males; (iii) both females and males respond similarly to treatment, showing significant improvements in anxiety and depression; (iv) APOE-3 carriers are the best responders and APOE-4 carriers tend to be the worst responders to conventional treatments; and (v) among CYP2D6, CYP2C19, and CYP2C9 genophenotypes, normal metabolizers (NMs) and intermediate metabolizers (IMs) are significantly better responders than poor metabolizers (PMs) and ultra-rapid metabolizers (UMs) to therapeutic interventions that modify anxiety and depression phenotypes in dementia. APOE-4 carriers and CYP-related PMs and UMs deserve special attention for their vulnerability and poor response to current treatments.
... From these studies, several conclusions can be drawn: (i) the age-at-onset is 5-10 years earlier in 80% of APOE-4/4 carriers; (ii) serum ApoE levels are lowest in APOE-4/4 carriers, intermediate in APOE-3/3 and APOE-3/4, and highest in APOE-2/3 and APOE-2/4 carriers; (iii) cholesterol levels are higher in patients harboring the APOE-4/4 genotype than in carriers of other genotypes; (iv) HDL-cholesterol levels tend to be lower in APOE-3 homozygotes than in APOE-4 allele carriers; (v) LDL-cholesterol levels are higher in APOE-4/4 carriers with an APOE genotype-related pattern similar to total cholesterol; (vi) serum triglycerides tend to show the lowest levels in APOE-4/4 carriers (vii) nitric oxide levels tend to show reduced values in APOE-4/4 carriers (viii) serum and CSF Aβ levels show differential patterns in APOE-4/4 carriers as compared with carriers of other genotypes (APOE-3/3, APOE-3/4); (ix) blood histamine levels are dramatically reduced in APOE-4/4 carriers; (x) brain atrophy and AD neuropathology are markedly increased in APOE-4/4 > APOE-3/4 > APOE-3/3; (xi) brain mapping activity shows increased slow wave activity in APOE-4/4 from early stages of the disease; (xii) brain hemodynamics (reduced brain blood flow velocity, increased pulsatility and resistance indices) is significantly worse in APOE-4 carriers than in APOE-3 carriers; brain hypoperfusion and neocortical oxygenation as assessed with optical topography mapping is also more deficient in APOE-4 carriers; (xiii) lymphocyte apoptosis is enhanced in APOE-4 carriers; (xiv) cognitive deterioration is faster in APOE-4/4 patients than in carriers of other APOE genotypes; (xv) some metabolic and hematological deficiencies (iron, ferritin, folic acid, vitamin B12) accumulate more in APOE-4 carriers than in APOE-3 carriers; (xvi) some behavioral disturbances, alterations in circadian rhythm patterns, and mood disorders are slightly more frequent in APOE-4 carriers; (xvii) aortic and systemic atherosclerosis is also more frequent in APOE-4 carriers and the size of atheroma plaques in the aorta wall tends to be almost two-fold higher in APOE-4/4 carriers; (xviii) liver metabolism and transaminase activity also differ in APOE-4/4 with respect to other genotypes; (xix) hypertension and other cardiovascular risk factors also tend to accumulate in carriers of the APOE-4 allele; and (xx) APOE-4/4 carriers are the poorest responders to conventional drugs. All these phenotypic features clearly illustrate the biological disadvantage of APOE-4 homozygotes and the potential consequences that these patients may experience when they receive pharmacological treatment for AD and/or concomitant pathologies [2][3][4]6,[112][113][114][115][116][117][118][119][120][121][122][123][124]. ...
... Different studies document the impact of APOE genotypes on AD therapeutics [2][3][4][5]7,19,121,122,[124][125][126][127]133]. We have performed prospective and retrospective studies in which it was clearly demonstrated that APOE-4 carriers are the worst responders to conventional treatments [2,3,6,118,120,127,134]. The TOMM40 locus is located near to and in linkage disequilibrium with the APOE locus on 19q13.2. ...
... CYP2D6 genophenotypes are highly influential in the response to cholinesterase inhibitors and other medications in AD [2,7,19,118,127,133,150]. In our sample, the distribution and frequency of CYP2D6 genophenotypes was as follows: Extensive metabolizers (EM), 59.46%; intermediate metabolizers (IM), 20.06%; poor metabolizers (PM), 5.36%; and ultra-rapid metabolizers (UM), 6.12% (Figure 17). ...
Sirtuins (SIRT1-7) are NAD+-dependent protein deacetylases/ADP ribosyltransferases with important roles in chromatin silencing, cell cycle regulation, cellular differentiation, cellular stress response, metabolism and aging. Sirtuins are components of the epigenetic machinery, which is disturbed in Alzheimer’s disease (AD), contributing to AD pathogenesis. There is an association between the SIRT2-C/T genotype (rs10410544) (50.92%) and AD susceptibility in the APOEε4-negative population (SIRT2-C/C, 34.72%; SIRT2-T/T 14.36%). The integration of SIRT2 and APOE variants in bigenic clusters yields 18 haplotypes. The 5 most frequent bigenic genotypes in AD are 33CT (27.81%), 33CC (21.36%), 34CT (15.29%), 34CC (9.76%) and 33TT (7.18%). There is an accumulation of APOE-3/4 and APOE-4/4 carriers in SIRT2-T/T > SIRT2-C/T > SIRT2-C/C carriers, and also of SIRT2-T/T and SIRT2-C/T carriers in patients who harbor the APOE-4/4 genotype. SIRT2 variants influence biochemical, hematological, metabolic and cardiovascular phenotypes, and modestly affect the pharmacoepigenetic outcome in AD. SIRT2-C/T carriers are the best responders, SIRT2-T/T carriers show an intermediate pattern, and SIRT2-C/C carriers are the worst responders to a multifactorial treatment. In APOE-SIRT2 bigenic clusters, 33CC carriers respond better than 33TT and 34CT carriers, whereas 24CC and 44CC carriers behave as the worst responders. CYP2D6 extensive metabolizers (EM) are the best responders, poor metabolizers (PM) are the worst responders, and ultra-rapid metabolizers (UM) tend to be better responders that intermediate metabolizers (IM). In association with CYP2D6 genophenotypes, SIRT2-C/T-EMs are the best responders. Some Sirtuin modulators might be potential candidates for AD treatment.
... The development of dermatoses in subjects with a predisposition to glucose intolerance could be influenced by rs2070600 [28]. An analysis of patients with type 1 diabetes Diabetic complications [38] Rheumatoid arthritis [32,[50][51][52] Cancer [54,56,57,59] Lung pathologies such as COPD and ARDS [69] Alzheimer's disease [75][76][77][78] Psychoticism factors [33] rs1800624 c. from the Finn Diane cohort has found that rs2070600 could predict an increased risk of type 1 diabetes, with an association with decreased circulating sRAGE levels [38]. ...
... These findings suggest that rs2070600 is probably a risk factor for the early onset of Alzheimer's disease [75]. Another analysis from a Chinese cohort showed a higher prevalence of rs2070600 in early-onset Alzheimer's disease patients [76,77]. Moreover, this result was also found in another study in which rs2070600 was associated with increased risk of Alzheimer's disease [78]. ...
The receptor for advanced glycation end-products (RAGE) is a cell surface transmembrane multiligand receptor, encoded by the AGER gene. RAGE presents many transcripts, is expressed mainly in the lung, and involves multiple pathways (such as NF κ B, Akt, p38, and MAP kinases) that initiate and perpetuate an unfavorable proinflammatory state. Due to these numerous functional activities, RAGE is implicated in multiple diseases. AGER is a highly polymorphic gene, with polymorphisms or SNP (single-nucleotide polymorphism) that could be responsible or co-responsible for disease development. This review was designed to shed light on the pathological implications of AGER polymorphisms. Five polymorphisms are described: rs2070600, rs1800624, rs1800625, rs184003, and a 63 bp deletion. The rs2070600 SNP may be associated with the development of human autoimmune disease, diabetes complications, cancer, and lung diseases such as chronic obstructive pulmonary disease and acute respiratory distress syndrome. The rs1800624 SNP involves AGER gene regulation and may be related to reduced risk of heart disease, cancer, Crohn’s disease, and type 1 diabetes complications. The rs1800625 SNP may be associated with the development of diabetic retinopathy, cancer, and lupus but may be protective against cardiovascular risk. The rs184003 SNP seems related to coronary artery disease, breast cancer, and diabetes. The 63 bp deletion may be associated with reduced survival from heart diseases during diabetic nephropathy. Here, these potential associations between AGER polymorphisms and the development of diseases are discussed, as there have been conflicting findings on the pathological impact of AGER SNPs in the literature. These contradictory results might be explained by distinct AGER SNP frequencies depending on ethnicity.
... In preclinical studies, LipoEsar has been shown to be effective in (i) reducing blood cholesterol, triglyceride, uric acid, and glucose levels, as well as liver alanine aminotransferase and aspartate aminotransferase activity; (ii) enhancing immunological function by regulating both lymphocyte and microglia activity; (iii) inducing antioxidant effects mediated by superoxide dismutase activity; and (iv) improving cognitive function [27,36,37,[40][41][42][43]. This LP displays a powerful effect on the regulation of lipid metabolism, especially by reducing total-cholesterol and LDL-cholesterol levels in cases of dyslipidemia or hypercholesterolemia [44][45][46][47][48]. E-SAR is an excellent cardioprotector and is effective in liver steatosis and in cases of primary or secondary transaminitis. ...
... This LP displays a powerful effect on the regulation of lipid metabolism, especially by reducing total-cholesterol and LDL-cholesterol levels in cases of dyslipidemia or hypercholesterolemia [44][45][46][47][48]. E-SAR is an excellent cardioprotector and is effective in liver steatosis and in cases of primary or secondary transaminitis. E-SAR has shown cognitive-enhancing properties in hypercholesterolemic patients with Alzheimer's disease [46]. The therapeutic response of patients with dyslipidemia to E-SAR is APOE-related ( Fig. 6.1). ...
... The best responders are APOE-3 carriers. In patients with dementia, the effects of LipoEsar are very similar to those observed in patients with chronic dyslipidemia, suggesting that the lipid-lowering properties of E-SAR are APOE-dependent [44,[46][47][48]. Recent studies also indicate that the hypolipemic effects of LipoEsar alone or in combination with atorvastatin (10 mg/day) are associated with polymorphic variants of the APOB (Fig. 6.2), APOC3 (Fig. 6.3), CEPT (Fig. 6.4), and LPL genes [48] ( Fig. 6.5), as demonstrated in dyslipidemic patients with different brain disorders (e.g., dementia, psychosis, stroke, depression, anxiety, Parkinson's disease) (Figs. ...
Fish consumption has represented a source of staple food for mankind over the
centuries. Different observations show that the health conditions of the population
are different in the coastal regions when compared with the regions of the
interior and highlands, especially regarding cardiovascular disorders, cancer,
and stroke [1]. While the health properties of the Japanese or Mediterranean
diets and of several vegetables are relatively well recognized by the medical
and the scientific community [2–4], much less is known about the biomedical
properties of marine derivatives and/or molecules isolated from biomarine
sources. However, a growing interest is emerging regarding the health properties
of fish [5] in contrast to the risk of abusive meat consumption worldwide
[1].
... The complexity of AD pathogenesis relies on the combination of genetic, epigenetic, and environmental factors. Current research accumulates data from over 600 single-nucleotide polymorphisms (SNPs), as well as Mendelian and mitochondrial mutations, in genes potentially associated with AD progression [13,[22][23][24]. Mendelian mutations affect AD pathogenic genes, including presenilins (PSEN1 and PSEN2), Aβ-precursor protein (APP), apolipoprotein E (APOE), and the alpha-2-macroglobulin (A2M). ...
... Polymorphic variants on PSEN1 and PSEN2 genes, detected in some AD patients, correlate with an impaired APP cleavage and Aβ aggregation into senile plates. Polymorphisms in the gene encoding the microtubule-associated protein tau (MAPT) promote tau protein hyperphosphorylation which results in microtubule destabilization leading to neurofibrillary degeneration [2,3,23,25]. Polymorphic variants in the gene encoding apolipoprotein E (APOE), which associate with hypercholesterolemia and vascular disorders, constitute one of the most relevant genetic hallmark s of AD. ...
... The A2M gene, encoding for the alpha-2-macroglobulin (a protease inhibitor), is also localized in amyloid plaques and interacts with Aβ and APOE. The polymorphism 2998 G > A (rs669) in homozygosis increases the risk for the onset of AD by 4-fold compared with the general population [23,25,26]. ...
Cerebrovascular and neurodegenerative disorders affect one billion people around the world and result from a combination of genomic, epigenomic, metabolic, and environmental factors. Diagnosis at late stages of disease progression, limited knowledge of gene biomarkers and molecular mechanisms of the pathology, and conventional compounds based on symptomatic rather than mechanistic features, determine the lack of success of current treatments, including current FDA-approved conventional drugs. The epigenetic approach opens new avenues for the detection of early presymptomatic pathological events that would allow the implementation of novel strategies in order to stop or delay the pathological process. The reversibility and potential restoring of epigenetic aberrations along with their potential use as targets for pharmacological and dietary interventions sited the use of epidrugs as potential novel candidates for successful treatments of multifactorial disorders involving neurodegeneration. This manuscript includes a description of the most relevant epigenetic mechanisms involved in the most prevalent neurodegenerative disorders worldwide, as well as the main potential epigenetic-based compounds under investigation for treatment of those disorders and their limitations.
... To date, the most influential gene in AD pharmacogenetics is the APOE gene [2,[6][7][8]10,16,17,24]. The vast majority of pharmacogenetic studies in AD have been performed with susceptibility genes (APOE) and metabolic genes (CYPs) [8,10,24,25]. ...
... To date, the most influential gene in AD pharmacogenetics is the APOE gene [2,[6][7][8]10,16,17,24]. The vast majority of pharmacogenetic studies in AD have been performed with susceptibility genes (APOE) and metabolic genes (CYPs) [8,10,24,25]. In general terms, APOE-3 carriers tend to be the best responders to conventional antidementia drugs (donepezil, rivastigmine, galantamine, and memantine), and APOE-4 carriers are the worst responders to different treatments [6][7][8]10,14,17,24,25]. ...
... The vast majority of pharmacogenetic studies in AD have been performed with susceptibility genes (APOE) and metabolic genes (CYPs) [8,10,24,25]. In general terms, APOE-3 carriers tend to be the best responders to conventional antidementia drugs (donepezil, rivastigmine, galantamine, and memantine), and APOE-4 carriers are the worst responders to different treatments [6][7][8]10,14,17,24,25]. The association of the TOMM40-L/L genotype with the APOE-4/4 genotype yields a haplotype (4/4-L/L) that is responsible for early onset of the disease, a faster cognitive decline, and a poor response to treatment [7,8,16,17]. ...
Alzheimer’s disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products. Only 20% of the Caucasian population are extensive metabolizers for tetragenic haplotypes integrating CYP2D6-CYP2C19-CYP2C9-CYP3A4/5 variants. Patients harboring CYP-related poor (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic (APOE-APOB-APOC3-CETP-LPL) haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG-AG-CC) exhibit the lowest cholesterol levels, and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Furthermore, APOE, NOS3, ACE, AGT, and CYP variants influence the therapeutic response to hypotensive drugs in AD patients with hypertension. Consequently, the implementation of pharmacogenetic procedures may optimize therapeutics in AD patients under polypharmacy regimes for the treatment of concomitant vascular disorders.
... APOE-4/4 carriers are regarded as the worst responders to conventional treatments (Poirrier et al., 1995;Cacabelos et al., 2014). In addition, roughly 10-20% of Caucasians bears genetic variations of cytochrome P450 enzymes (e.g., CYP1A1, CYP2E1 and many others); with a focus on CYP2D6 polymorphic variants that can induce alterations in drug metabolism and alter the efficacy and safety of the prescribed drug (Cacabelos et al., 2010). ...
Alzheimer's disease ( AD ) belongs to one of the most multifactorial, complex and heterogeneous morbidity‐leading disorders. Despite the extensive research in the field, AD pathogenesis is still at some extend obscure. Mechanisms linking AD with certain comorbidities, namely diabetes mellitus, obesity and dyslipidemia, are increasingly gaining importance, mainly because of their potential role in promoting AD development and exacerbation. Their exact cognitive impairment trajectories, however, remain to be fully elucidated. The current review aims to offer a clear and comprehensive description of the state‐of‐the‐art approaches focused on generating in‐depth knowledge regarding the overlapping pathology of AD and its concomitant ailments. Thorough understanding of associated alterations on a number of molecular, metabolic and hormonal pathways, will contribute to the further development of novel and integrated theranostics, as well as targeted interventions that may be beneficial for individuals with age‐related cognitive decline.
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... The PSEN1 and PSEN2 genes, encoding presenilin1 and 2, are important determinants of the β-secretase activity responsible for proteolytic cleavage of the Aβ-precursor protein (APP). Mutations in the PSEN1, PSEN2, and APP confer phenotypes of amyloidogenic pathology and dementia [19,42,43,45]. One of the most prevalent risk genes in AD is the APOE, especially in those individuals harboring the APOE-ε4 allele [13,19,44,46]. ...
... The A2M gene, encoding for the alpha-2-macroglobulin (a protease inhibitor), is also localized in amyloid plaques and interacts with Aβ and APOE. The polymorphism 2998G>A (rs669) in ho-mozygosis increases the risk for the onset of AD by 4-fold when compared to the general population [13,19,45]. ...
... Nevertheless, besides the prevalence of APOE-ε4, there are also other good reasons to suggest that our population may have a higher rate of individuals with a potential onset of AD than previously expected: (i) Polymorphism +16G>T (rs165932) in the PSEN1 gene is also prevalent in our population compared to other representative Spanish and European populations ( Table 3). This polymorphism is a hallmark of AD, since it affects β-secretase activity leading to accumulation of Aβ. [19,42,43,45]. (ii) Contrary to APOE-ε4, carriers of APOE-ε2 may be protected against dementia, and in fact, APOE-ε2 allele distribution is usually lower in individuals with AD [13,19,44]. ...
Introduction:
Cardiovascular and neurodegenerative disorders are among the major causes of mortality in the developed countries. Population studies evaluate the genetic risk, i.e. the probability of an individual carrying a specific disease-associated polymorphism. Identification of risk polymorphisms is essential for an accurate diagnosis or prognosis of a number of pathologies.
Aims:
The aim of this study was to characterize the influence of risk polymorphisms associated with lipid metabolism, hypertension, thrombosis, and dementia, in a large population of Spanish individuals affected by a variety of brain and vascular disorders as well as metabolic syndrome.
Material & method:
We performed a cross-sectional study on 4415 individuals from a widespread regional distribution in Spain (48.15% males and 51.85% females), with mental, neurodegenerative, cerebrovascular, and metabolic disorders. We evaluated polymorphisms in 20 genes involved in obesity, vascular and cardiovascular risk, and dementia in our population and compared it with representative Spanish and European populations. Risk polymorphisms in ACE, AGT(235), IL6(573), PSEN1, and APOE (specially the APOE-ε4 allele) are representative of our population as compared to the reference data of Spanish and European individuals.
Conclusion:
The significantly higher distribution of risk polymorphisms in PSEN1 and APOE-ε4 is characteristic of a representative number of patients with Alzheimer's disease; whereas polymorphisms in ACE, AGT(235), and IL6(573), are most probably related with the high number of patients with metabolic syndrome or cerebrovascular damage.
